Resseguie Emily A, Staversky Rhonda J, Brookes Paul S, O'Reilly Michael A
Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA.
Department of Pediatrics, University of Rochester, Rochester, NY 14642, USA.
Redox Biol. 2015 Aug;5:176-185. doi: 10.1016/j.redox.2015.04.012. Epub 2015 May 2.
High levels of oxygen (hyperoxia) are often used to treat individuals with respiratory distress, yet prolonged hyperoxia causes mitochondrial dysfunction and excessive reactive oxygen species (ROS) that can damage molecules such as DNA. Ataxia telangiectasia mutated (ATM) kinase is activated by nuclear DNA double strand breaks and delays hyperoxia-induced cell death through downstream targets p53 and p21. Evidence for its role in regulating mitochondrial function is emerging, yet it has not been determined if mitochondrial dysfunction or ROS activates ATM. Because ATM maintains mitochondrial homeostasis, we hypothesized that hyperoxia induces both mitochondrial dysfunction and ROS that activate ATM. In A549 lung epithelial cells, hyperoxia decreased mitochondrial respiratory reserve capacity at 12h and basal respiration by 48 h. ROS were significantly increased at 24h, yet mitochondrial DNA double strand breaks were not detected. ATM was not required for activating p53 when mitochondrial respiration was inhibited by chronic exposure to antimycin A. Also, ATM was not further activated by mitochondrial ROS, which were enhanced by depleting manganese superoxide dismutase (SOD2). In contrast, ATM dampened the accumulation of mitochondrial ROS during exposure to hyperoxia. Our findings suggest that hyperoxia-induced mitochondrial dysfunction and ROS do not activate ATM. ATM more likely carries out its canonical response to nuclear DNA damage and may function to attenuate mitochondrial ROS that contribute to oxygen toxicity.
高氧水平（高氧血症）常用于治疗呼吸窘迫患者，但长时间的高氧血症会导致线粒体功能障碍和过量的活性氧（ROS），进而损害DNA等分子。共济失调毛细血管扩张症突变（ATM）激酶可被核DNA双链断裂激活，并通过下游靶点p53和p21延迟高氧诱导的细胞死亡。其在调节线粒体功能方面作用的证据正在显现，但线粒体功能障碍或ROS是否激活ATM尚未确定。由于ATM维持线粒体稳态，我们推测高氧血症会诱导线粒体功能障碍和ROS，进而激活ATM。在A549肺上皮细胞中，高氧血症在12小时时降低了线粒体呼吸储备能力，在48小时时降低了基础呼吸。ROS在24小时时显著增加，但未检测到线粒体DNA双链断裂。当通过长期暴露于抗霉素A抑制线粒体呼吸时，激活p53不需要ATM。此外，线粒体ROS不会进一步激活ATM，而通过消耗锰超氧化物歧化酶（SOD2）可增强线粒体ROS。相反，在暴露于高氧血症期间，ATM可抑制线粒体ROS的积累。我们的研究结果表明，高氧血症诱导的线粒体功能障碍和ROS不会激活ATM。ATM更可能对核DNA损伤进行其典型反应，并可能起到减弱导致氧毒性的线粒体ROS的作用。
